Drug Therapy Flashcards
Discuss Th1 cells role in immunity
- CD4 T cell
- increase cell-mediated response
- triggered by IL -12
- effector cytokines IFN-gamma and IL-2
- IFN- gamma activates macrophages
- CD 8 T cells, IgG B cells, and IFN-gamma CD4 T cell
Discuss Th2 cells role in immunity
- Trigger a humoural immune response
- Triggered by IL-5 and IL-2
- effector cytokines include: IL - 4, 5, 9, 10, 13, 25
- Effector cells include eosinophils, basophils and mast cells
- Also trigger B cells
- effect IL4/IL5 CD4 T cells
List triggers for immune mediated disease
- Genetic factors
- MHC class
- Environmental factors - including exposure to UV light, allergens such as fleas, pollens, dust mites
- Drug exposure
- cephalosporins, TMS
- Infection:
- Rickettsial infection
- Borellia
- Anaplasma
- Viruses including calicivirus, FeLV
What is the primary pathogenesis in haematological immune mediated disease?
- Th2 mediated, humoral immune response with over production of auto-antibody directed against cell surface antigens
How are haematological cells destroyed by a humoral immune response
- Th2 mediated stimulation of B cells to produce auto-antibody
- Auto antibody causes opsonisation of the target cell
- Subsequent activation of complement and destruction/removal via the reticuloendothelial system
Discuss basic mechanism of action of immunosuppressive medications
- Reduce antibody production by B cells
- Reduce clearance of opsonised cells by macrophages
- Reduce activation of the complement cascade
Mechanism of action: glucocorticoids - cardiovascular
- Reduced capillary permeability
- Enhanced vasoconstriction
- Increase BP due to vasoconstriction and increased blood volume
Mechanism of action: glucocorticoids - Cells
- Inhibit fibroblast proliferation
- Inhibit macrophage response to migration inhibiting factor
- Inhibit sensitisation of lymphocytes
- Inhibit the cellular response to inflammatory mediators
- Stabilise lysosomal membranes
Mechanism of action: glucocorticoids - CNS
- Alter mood and behaviour
- Reduce seizure threshold
- Diminish the response to pyrogens
- Stimulate appetite
- Necessary for normal adrenergic receptor sensitivity
Mechanism of action: glucocorticoids - Endocrine
- Suppress the release of ACTH
- Reduce release of - TSH, FSH, LH and prolactin
- Maybe reduce conversion of T4 to T3
- Increase plasma PTH levels
- Inhibit osteoblast function 6.
- ADH activity is suppressed at the renal tubules - lead to diuresis
- Inhibit insulin binding to insulin receptors
- Inhibit post-receptor effects of insulin
Mechanism of action: glucocorticoids - Haematopoietic System
- Increase numbers of platelets, neutrophils and red blood cells in circulation 2. Decrease peripheral lymphocyte numbers 3. Decreased monocytes and eosinophils 4. causes sequestration of lymhpocytes, eosinophils and monocytes in the lung and spleen. 5. Reduced release of above cells from the bone marrow 6. Reduces clearance of old red blood cells 7. Can cause involution of lymphoid tissue
Mechanism of action: glucocorticoids - GIT tract
- Increased secretion of gastric acid, trypsin and pepsin 2. Altered mucin structure 3. Decrease mucosal cell proliferation 4. Iron and calcium absorption is decreased 5. Fat absorption is increased
Mechanism of action: glucocorticoids - Liver
- Increase fat storage 2. Increased glygogen deposition 3. Increase serum levels of ALT, GGT and significant increases in ALKP
Mechanism of action: glucocorticoids - Immune System
nb. Most effects are potentiated by high or very high doses. nb. Specific acquired immunity is less affected than non-specific immune responses 1. ↓ circulating levels of T cell 2. Inhibit lymphokines 3. Inhibit neutrophil, monocyte and macrophage migration 4. Reduce interferon production 5. Inhibit phagocytosis and chemotaxis 6. Inhibit antigen processing 7. Diminish intracellular killing 8. Antagonize the complement cascade 9. Mask clinical signs of infection 10. Mast cells numbers are decreased and histamine release suppressed.
Mechanism of action: glucocorticoids - Metabolic effects
- Lipogenesis in enhanced in the abdomen 2. Fat redistribution to trunk from the extremities 3. Fatty acids are mobilized 4. Increase plasma levels of triglycerides, cholesterol and glycerol. 5. Protein is mobilized
Mechanism of action: glucocorticoids - Musculoskeletal effects
- Can cause muscular atrophy and weakness 2. Osteoporosis (due to reduced osteoblast function) 3. Bone growth can be inhibited - growth hormone and somatomedin inhibition, increased calcium excretion and inhibition of vitamin D activation 4. Bone resorption can be enhanced 5. Fibrocartilage growth inhibited
Mechanism of action: glucocorticoids - Renal
- Increased potassium and calcium excretion 2. Increased sodium and chloride retention 3. Potentiate increased extracellular fluid volume 4. Stimulate diuresis (via ADH antagonism)
Mechanism of action: glucocorticoids - Skin / eye
- Thinning of dermal tissue and atrophy 2. Hair follicle distension (can see comedones) 3. Alopecia 4. prolonged use can cause glaucoma, cataracts and exophthalmos
Cyclosporin A - mechanism of action
Inhibitor of calcineurin which ultimately supresses the kinase cascade 1. Suppresses primarily cell mediated immunity (non-Ab) 2. Reversible inhibition of immunocompetent lymphocytes in the G0-G1 phase of the cell cycle 3. T-helper cells are the primary target 4. Reduces lymphokine production - especially IL-2 and T-cell growth factor
Azathioprine - mechanism of action
- Antaganises purine metabolism 2. Inhibits RNA, DNA synthesis and mitosis 3. May cause chromosome breaks by incorporation into nucleic acids 4. Inhibits coenzyme formation 5. Greater response on cell mediated immunity and delayed hypersensitivity (cf humoral immunity)
Mycophenolate - mechanism of action
Nycophenolate is an inhibitor of purine synthesis
- Prodrug that is converted to mycophenolic acid (MPA)
- Non-competitive, reversible inhibitor of inosine monophosphatate dehydrogenase (IMPDHA)
- IMPDHA responsible for the rate limiting step in de novo synthesis of guanosine nucleotides.
- B and T cells are dependent of de novo purine synthesis
- Inhibits proliferation of T- and B-cell lymphocytes
- Suppresses B-cell formation of antibodies
- Can inhibit leukocyte recruitment to sites of inflammation
Leflunomide: mechanism of action
- Acts through metabolite A77 1726 (M1) 2. M1 reversibly binds to the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) 3. Decreased DHODH function prevents formation of ribonucleotide uridine monophosphate 4. DHODH is the rate limitings enzyme in de novo pyrimidine synthesis. 5. Causes reduced DNA and RNA synthesis, inhibition of cell cycle proliferation and G1 cell cycle arrest
